Small molecule inhibitors of dynamin I GTPase activity : Development of dimeric tyrphostins

Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a μM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 μM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low μM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic −OHs:  catechol-acrylamide (9) (IC50 = 5.1 ± 0.6 μM), its 3,4,5-trihydroxy congener (10) (IC50 = 1.7 ± 0.2 μM), and the corresponding 3-methyl ether (11) (IC50 = 9 ± 3 μM). Increasing the length of the central alkyl spacer from ethyl to propyl (22−24) afforded essentially identical activity with IC50's of 1.7 ± 0.2, 1.7 ± 0.2, and 5 ± 1 μM, respecti...